The impact of low-frequency and rare variants on lipid levels.

Nat Genet
Authors
Ida Surakka
Momoko Horikoshi
Reedik Mägi
Antti-Pekka Sarin
Anubha Mahajan
Vasiliki Lagou
Letizia Marullo
Teresa Ferreira
Benjamin Miraglio
Sanna Timonen
Johannes Kettunen
Matti Pirinen
Juha Karjalainen
Gudmar Thorleifsson
Sara Hägg
Jouke-Jan Hottenga
Aaron Isaacs
Claes Ladenvall
Marian Beekman
Tõnu Esko
Janina Ried
Christopher Nelson
Christina Willenborg
Stefan Gustafsson
Harm-Jan Westra
Matthew Blades
Anton de Craen
Eco de Geus
Joris Deelen
Harald Grallert
Anders Hamsten
Aki Havulinna
Christian Hengstenberg
Jeanine Houwing-Duistermaat
Elina Hyppönen
Lennart Karssen
Terho Lehtimäki
Valeriya Lyssenko
Patrik Magnusson
Evelin Mihailov
Martina Müller-Nurasyid
John-Patrick Mpindi
Nancy Pedersen
Brenda Penninx
Markus Perola
Tune Pers
Annette Peters
Johan Rung
Johannes Smit
Valgerdur Steinthorsdottir
Martin Tobin
Natalia Tšernikova
Elisabeth van Leeuwen
Jorma Viikari
Sara Willems
Gonneke Willemsen
Heribert Schunkert
Jeanette Erdmann
Nilesh Samani
Jaakko Kaprio
Lars Lind
Christian Gieger
Andres Metspalu
P Eline Slagboom
Leif Groop
Cornelia van Duijn
Johan Eriksson
Antti Jula
Veikko Salomaa
Dorret Boomsma
Christine Power
Olli Raitakari
Erik Ingelsson
Marjo-Riitta Jarvelin
Unnur Thorsteinsdottir
Lude Franke
Elina Ikonen
Olli Kallioniemi
Vilja Pietiäinen
Cecilia Lindgren
Kari Stefansson
Aarno Palotie
Mark McCarthy
Andrew Morris
Inga Prokopenko
Samuli Ripatti
ENGAGE Consortium
Keywords
Humans
Gene Frequency
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Dyslipidemias
Linkage Disequilibrium
Sequence Analysis, DNA
Genetic Loci
Lipid Metabolism
Mutation, Missense
Abstract

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
Year of Publication
2015
Journal
Nat Genet
Volume
47
Issue
6
Pages
589-97
Date Published
2015 Jun
ISSN
1546-1718
URL
http://dx.doi.org/10.1038/ng.3300
DOI
10.1038/ng.3300
PubMed ID
25961943
PubMed Central ID
PMC4757735
Links
Grant list
098017 / Wellcome Trust / United Kingdom
British Heart Foundation / United Kingdom
076113 / Wellcome Trust / United Kingdom
064890 / Wellcome Trust / United Kingdom
G0902313 / Medical Research Council / United Kingdom
WT090532 / Wellcome Trust / United Kingdom
WT098017 / Wellcome Trust / United Kingdom
WT064890 / Wellcome Trust / United Kingdom
069224 / Wellcome Trust / United Kingdom

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